Continued development in contrast media is finally beginning to pay off as experts aim for an ideal agent.

The ideal contrast agent should have negligible side effects, be easily and quickly eliminated by the body, and should not cause contrast-induced nephropathy (CIN). In certain conditions, organ- and tissue-specific enhancement is preferable,” said Numan Balci, MD, associate professor of radiology at the Saint Louis University School of Medicine in St Louis. Balci summarizes the opinion of many physicians who rely on imaging to make diagnostic, prognostic, and treatment decisions.

“I think most people would argue that we need more specific contrast agents, whether organ-specific, disease-specific, or mechanism-specific,” said King Li, MD, MBA, FRCP, MD Anderson Foundation Distinguished Chair in Radiology and Imaging Sciences; professor of radiology at Weill Cornell Medical College in New York; adjunct professor of bioengineering at Rice University in Houston; adjunct professor of mechanical engineering at the University of Houston; and chair of the department of radiology at The Methodist Hospital, also in Houston.

Li suggests that MRI and CT organ-specific contrast agents lag behind those used in nuclear medicine, and more development by manufacturers would help, particularly with differential diagnostics throughout the body.

Manufacturers are not deaf to these demands, and they have been at work developing new agents. Unfortunately, over the past decade, the FDA has approved very few organ-specific contrast agents. One of the obstacles any new contrast agent faces is the success of the old agents.

“There are instances—for example, iodinated contrast agents for CT—where the original type of agent approved has proved to be so effective in many ways that it has been very hard to improve on that. So the attempts to come up with organ-specific or disease-specific agents to date have not been successful because they have not provided enough incremental benefit over existing agents,” Brown said.

That, however, is changing. Manufacturers have been challenged to develop agents that significantly improve the safety and/or efficacy of the existing contrast agents and to prove it (often with a large-scale, multicentric study). And some are making significant progress.

Bayer HealthCare Pharmaceuticals Inc, Wayne, NJ, can claim the first FDA approval of an organ-specific contrast agent in more than a decade. The company recently received FDA approval for Eovist (gadoxetate disodium) Injection, a gadolinium-based contrast agent for intravenous use in T1-weighted MRI of the liver to detect and characterize lesions in adults with known or suspected focal liver disease.

GE Healthcare, Waukesha, Wis, is also at work on improving agent options. A study published in the journal Radiology this summer looked at the impact of GE’s isomolar contrast medium iodixanol on serum creatinine levels and included findings that some think illustrate a potential for reduced risk of adverse outcomes. Not everyone agrees with these findings, but many concur more research is needed.

New Agent Approved

Significant research is needed for most new agents to prove their value. As part of its FDA submission, Bayer completed four nonrandomized, intrapatient-controlled clinical trials that evaluated Eovist’s impact on the detection and morphological characterization of liver lesions using MRI. Eovist-contrasted MRI was compared to precontrast MRI exams and was found to improve efficacy.

“Most of the time, when we see something in the liver, we want to know if it is benign or malignant. If it is malignant, we want to know if it’s a primary cancer or metastasized. If benign, we want to know what specific benign lesion we are looking at because some may need more attention than others. Having liver-specific contrast agents would help in making that decision,” Li said.

Eovist is a paramagnetic MRI contrast agent that combines the features of an extracellular contrast agent and a hepatocyte-specific agent. Administered via an intravenous, bolus injection, roughly half of the dose is eliminated via the kidney and the other half through the liver. “Because the new agent is secreted by normal liver cells, you can see lesions that do not contain normal liver cells much easier—as a hole in the liver,” Li said.

“Eovist-enhanced images can provide more comprehensive information about focal liver lesions in a single, short imaging session than was previously available,” Brown concurred. He suggests the ability to detect and differentiate lesions can be improved, particularly the detection of smaller lesions and the differentiation of cells with and without podocyte function.

Balci had used Eovist while practicing in Europe, where the agent has been approved since 2004, and found it offered several advantages that include a lower dose, a high relaxivity, and usefulness in both the extracellular space and the hepatobiliary system. “The hepatobiliary phase of the contrast agent starts at 28 minutes after the injection,” Balci said. This means the patient can stay in the scanner to acquire the hepatobiliary images, rather than leaving and returning an hour or so later.

The risks of Eovist are the same as with other gadolinium-containing contrast agents. “The safety profile is very similar to the current agents on the market, so we don’t anticipate any difference in general adverse events. These agents have historically been safe,” Brown said.

The four clinical trials used in the FDA submission show the new contrast medium was well tolerated with 4.3% of 1,755 adult subjects overall reporting an adverse event. Of these, six were serious, occurred more than 10 hours later, and were attributed to underlying conditions or non-MRI procedures.

The company does not yet have data to show any improvements in the safety profile, but some suspect that because Eovist uses the liver pathway for excretion, it may lower the risk of potentially adverse events. “Other agents are excreted almost exclusively by the kidneys and can’t get out of the body quickly, but Eovist is excreted through the liver. So if the kidneys aren’t working, there is another pathway to help eliminate the agent from the body,” Brown said.

Other characteristics help too. “Because the agent is eliminated by both the liver and kidney, we can lower the dose. The lower dose combined with the high relaxivity could potentially lower the risk of nephrogenic systemic fibrosis [NSF],” Balci said.

New Study Examined

Contrast agents have not been definitively linked to NSF, but current thought suggests the two are related, particularly in patients with existing kidney conditions at the time of the imaging exam. The evidence is suggestive enough that the FDA added a boxed warning on the labels of all gadolinium-based agents in 2007. The warning refers to the risk of NSF for patients with acute or chronic severe renal insufficiency and/or with acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period.

Naturally, there have been a number of studies that have examined this connection and compared the safety profiles of various contrast agents. One published in the journal Radiology this summer compared the effect of iodixanol (an iso-osmolar agent) and iopromide (a low-osmolar contrast medium) on serum creatinine levels.

A team of physicians and researchers at the Medical University of South Carolina, Charleston, evaluated 117 patients with decreased renal function who underwent contrast-enhanced CT studies; 61 patients were administered iodixanol, and 56 were given iopromide. Changes in the serum creatinine levels and glomerular filtration rate were measured at 1-, 2-, and 3-day intervals after the CT with outcomes were reviewed at 30 and 90 days.

The study found that while intravenous contrast material application in high-risk patients was unlikely to be associated with permanent adverse outcomes (no patients in either group showed a contrast media-related adverse event at the 30-day and 90-day marks), serum creatinine levels after contrast material administration were lower in the iodixanol group than in the iopromide group.

“This study shows that iodixanol was statistically significant in decreasing serum creatinine on day 1 and trended lower on days 2 and 3,” said Lauren Lim, PharmD, medical director for GE Healthcare. She suggests this translates into lower contrast-induced nephropathy or CIN.

“We don’t actually have trials to show this difference, but the study does show something about CIN,” Lim said. She defines CIN as the acute deterioration of renal function after the administration of iodinated contrast medium in the absence of other causes. The condition is associated with short-term and long-term morbidity and mortality.

“Since iodixanol is iso-osmolalar and has a lower impact on serum creatinine levels, it can be safer to use in patients with renal impairment or higher serum creatinine levels, and this may be associated to a lesser degree with contrast-induced nephropathy, but it should be proven and compared with the other agents,” said Balci, who notes the Radiology study lacks direct data on CIN. He would like to see the incidence of CIN compared among several groups of CT contrast agents.

Others would also like to see more research. “I think it is still controversial whether this contrast agent iodixanol is actually any better in terms of nephrotoxicity. We can’t look at one journal article but must look at all the available literature before making a decision. Other studies doing similar stuff and looking at similar patient populations did not find any difference,” Li said.

Richard Solomon, MD, professor of medicine at the University of Vermont School of Medicine in Burlington, cites studies that looked at intravenous contrast exposure and CIN that contrast the results of the Radiology study (these include the ACTIVE trial, published in the March 2008 issue of Investigative Radiology, and the PREDICT study, released in the July 2008 issue of the American Journal of Roentgenology). “These were all prospective randomized, multicenter trials that came up pretty much with similar incidences of contrast-induced nephropathy, which were in the five-percent range,” Solomon said.

The big difference between this study and the others, both the authors and critics are quick to point out, is the serum creatinine level measurement of day 1. Prior studies have often started measurements on day 2 or 3, and some have taken only that one. “When taking only one level, you are not getting a true reflection of the CIN rate,” Lim suggested.

Solomon believes, however, that the day 1 measurement may be irrelevant. “It takes until day 2 or 3 if it is contrast related,” Solomon said, suggesting that the results related to day 1 are likely related to something else. “We have three other trials that are all consistent in what they find, which suggests that there is no difference between iso-osmolar and low osmolar agents,” Solomon said. He adds that the Radiology paper also found no difference in outcome, suggesting the day 1 differences are irrelevant.

Lim answers these criticisms by pointing out the design flaws in these studies, including the low number of measurements and small sample sizes. “A lot of these studies are designed to show a difference, and to show difference, you need a huge number in the sample. But a lot of these studies have small sample sizes and are unable to show the difference. Inability to show difference is not the same as the ability to show equivalence,” Lim said.

Ultimately, each physician will have to make a decision regarding which contrast agent to use, taking into account not only the research but also the patient. “When one chooses a contrast medium for a patient, he should look at the contrast media as a whole to select the right contrast agent for the right patient,” Lim said.

These factors include data on patient comfort, heart rate disruption, and cardiac adverse events.

Renee Diiulio is a contributing writer for Medical Imaging. For more information, contact .